Dendritic cells (DCs) are the "sentinels" of the skin and mucosa, patrolling these tissues for invading bacteria and viruses. In their immature stage, DCs are uniquely equipped for antigen (Ag) capture, expressing a large variety of scavenger receptors and other pattern recognition receptors. As they mature and migrate to the lymph nodes, DCs downregulate Ag-capture receptors and upregulate Ag-presenting receptors. Mature DCs are the most efficient Ag-presenting cells (APCs), and the only APCs capable of stimulating naive T cells. The role of dendritic cell subpopulations in chronic periodontitis (CP); however, was largely unknown prior to these funded studies. Our lab has thus far published 11 papers, with 3 in preparation that can be credited to this R01, which terms in November of 2005. Our studies have identified an important role for gingival immature DC in the recognition and uptake of Porphyromonas gingivalis (Pg) in situ and in vitro, and for maturing DCs in engagement with CD4+ T cells in the gingival lamina propria. The principle DCs in the gingival lamina propria in CP are those that express DC-specific ICAM-3 grabbing non-integrinpositive (DC- SIGN) in CP. DC-SIGN is a member of a family of C-type lectins; it is a type II transmembrane receptor that is used as an "escape mechanism" by major human pathogens including HIV-1, Helicobacter pylori, Klepsiella pneumonia, M tuberculosis, Leishmania pifanoi and C albicans. A central feature of pathogens that target DC-SIGN is that they cause infections that can last a lifetime (i.e. such as CP) and secondly, that manipulation of the Th1- versus Th2-balance by these pathogens is central to their persistence. We have evidence that Pg and its PAMPs may target C-type lectin receptors on DCs and manipulate the Th1-Th2 balance; we hypothesize that this is involved in persistence of Pg in the oral mucosa. These proposed continued studies will therefore focus on the role of C-type lectins and other pattern recognition receptors (PRR) in uptake/recognition of Pg, its PAMPs and in intracellular routing by MDDCs and how this modulates the adaptive immune response, in particular, the induction of T regulatory cells.